Effect of dietary fat and the circadian clock on the expression of brain-derived neurotrophic factor (BDNF)

Mol Cell Endocrinol. 2016 Jul 15;430:49-55. doi: 10.1016/j.mce.2016.04.015. Epub 2016 Apr 22.

Abstract

Brain-derived neurotrophic factor (BDNF) is the most abundant neurotrophin in the brain and its decreased levels are associated with the development of obesity and neurodegeneration. Our aim was to test the effect of dietary fat, its timing and the circadian clock on the expression of BDNF and associated signaling pathways in mouse brain and liver. Bdnf mRNA oscillated robustly in brain and liver, but with a 12-h shift between the tissues. Brain and liver Bdnf mRNA showed a 12-h phase shift when fed ketogenic diet (KD) compared with high-fat diet (HFD) or low-fat diet (LFD). Brain or liver Bdnf mRNA did not show the typical phase advance usually seen under time-restricted feeding (RF). Clock knockdown in HT-4 hippocampal neurons led to 86% up-regulation of Bdnf mRNA, whereas it led to 60% down-regulation in AML-12 hepatocytes. Dietary fat in mice or cultured hepatocytes and hippocampal neurons led to increased Bdnf mRNA expression. At the protein level, HFD increased the ratio of the mature BDNF protein (mBDNF) to its precursor (proBDNF). In the liver, RF under LFD or HFD reduced the mBDNF/proBDNF ratio. In the brain, the two signaling pathways related to BDNF, mTOR and AMPK, showed reduced and increased levels, respectively, under timed HFD. In the liver, the reverse was achieved. In summary, Bdnf expression is mediated by the circadian clock and dietary fat. Although RF does not affect its expression phase, in the brain, when combined with high-fat diet, it leads to a unique metabolic state in which AMPK is activated, mTOR is down-regulated and the levels of mBDNF are high.

Keywords: AMPK; BDNF; Circadian clock; Ketogenic diet; Metabolism; Timed feeding.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylate Kinase / metabolism
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Brain-Derived Neurotrophic Factor / genetics*
  • Brain-Derived Neurotrophic Factor / metabolism
  • Circadian Clocks / drug effects
  • Circadian Clocks / genetics*
  • Dietary Fats / pharmacology*
  • Feeding Behavior / drug effects
  • Gene Expression Regulation / drug effects
  • Gene Knockdown Techniques
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Mice, Inbred C57BL
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptor, trkB / metabolism
  • Receptors, Nerve Growth Factor / metabolism
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Time Factors

Substances

  • Brain-Derived Neurotrophic Factor
  • Dietary Fats
  • RNA, Messenger
  • Receptors, Nerve Growth Factor
  • TNFRSF16 protein, mouse
  • Receptor, trkB
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Adenylate Kinase